The chronic non-medical use of cocaine has currently reached epidemic proportions despite numerous drug-related health problems and severe penalties associated with the possession and sale of the drug. This increase in compulsive cocaine use has resulted in considerable interest in the clinical and neurobiological implications of this behavior. Unfortunately, however, a clear-cut consensus among health care professionals has not yet evolved regarding optimal treatment strategies for cocaine abuse. The increase in the number of people suffering from cocaine dependence who have requested medical assistance for withdrawal has resulted in a number of investigations attempting to develop more satisfactory treatment strategies. A better understanding of the complex neurobiological changes associated with chronic cocaine intoxication may assist in the search for improved methods of treatment in the clinic. In addition, the chronic use of cocaine and related stimulants can result in a paranoid psychosis in some individuals. These psychoses are difficult to distinguish from paranoid schizophrenia when these drugs are taken long enough at high enough doses. If the chronic use of cocaine results in alterations in the central nervous system that are analogous to the neuropathology associated with schizophrenia, then a better understanding of these changes may increase knowledge of the etiology of mental illness and may therefore lead to the more effective and efficient treatment and management not only of drug dependence, but also of schizophrenia and related disorders. Finally, while not all chronic users of cocaine manifest psychoses or other psychiatric dysfunctions, the continued use of this drug may result in neurobiological alterations which may affect performance in the work place. A better understanding of the behavioral and corresponding neurobiological effects of chronic exposure to the drug, especially resulting from self-administered cocaine, may therefore assist in the identification of these drug-related problems in the work place and may indicate potential treatment strategies for these problems. The experiments proposed in this application will examine the neurobiological consequences of chronic cocaine intoxication using a multidisciplinary approach involving behavioral pharmacology, neurochemistry and neuroanatomy. The potential development of tolerance or sensitization to the effects of repeated injections of both non-contingent as well as self- administered cocaine on stereotypy and schedule-controlled behavior will be investigated. The involvement of receptor systems in the progressive development of this behavioral tolerance or sensitization will be determined by quantitative autoradiographic analyses of binding sites for various receptor systems in serial sections through the brain of each rat. Specific pharmacological interventions, neurotoxic lesions and in vivo microdialysis will be used to investigate the involvement of discrete brain regions and neurotransmitter systems in the behavioral pathology associated with chronic cocaine intoxication. These experiments will result in a better understanding of the behavioral, pharmacological, neurochemical and neuroanatomical consequences resulting from chronic exposure to the drug.